tbuckley/cabot-search huggingface dataset:
Abstract 3071: Pituitary adenylate cyclase activating polypeptide stimulates NSCLC growth by increasing HER4 tyrosine phosphorylation in a neuregulin-1 dependent manner
Authors: Terry W. Moody, Irene Ramos Alvarez, Robert T. Jensen
Journal: Cancer Research (2023)

Abstract Pituitary adenylate cyclase activating polypeptide [PACAP] is a 27 amino acid peptide which stimulates the growth of numerous cancers including non-small cell lung cancer (NSCLC). PACAP binds with high affinity to the type B G protein-coupled receptor [GPCR] PAC1 (Moody et al., Peptides 2021; 137: 170480). PAC1 activation causes phosphatidyl inositol [PI] turnover stimulating matrix metalloprotease [MMP]. By ELISA, PACAP increased secretion of neuregulin [NRG1] from NSCLC cells. NRG1 binds with high affinity to HER4. Here the ability of PAC1 to regulate transactivation of HER4 was investigated. By RT-PCR and Western blot, PAC1, NRG1 and HER4 but not HER3 or NRG2 were detected in NCI-H522 and H661 cells. Adding PACAP-27 (0.1 μM) or NRG1 (0.01 μg/ml) to NCI-H522 or H661 cells increased P-Tyr1284-HER4 3-fold after 5 min. Using immunoprecipitation techniques, adding PACAP TO NSCLC cells increased formation of HER4 homodimers and HER4-EGFR as well as HER4-HER2 heterodimers. The increase in P-HER4 caused by PACAP-27 was impaired by PACAP(6-38) [PAC1 antagonist], HER4 siRNA, NRG1 antibody [Ab] or ibrutinib [TKI]. The PAC1 regulation of HER4 transactivation is impaired by GM6001 [MMP inhibitor]. The clonal growth of NSCLC cells was stimulated by PACAP-27 or NRG1 but inhibited by PACAP(6-38) or ibrutinib. The results indicate that PACAP-27 stimulates the growth of NSCLC due to release of NRG1 which activates receptor tyrosine kinases such as HER4. Citation Format: Terry W. Moody, Irene Ramos Alvarez, Robert T. Jensen. Pituitary adenylate cyclase activating polypeptide stimulates NSCLC growth by increasing HER4 tyrosine phosphorylation in a neuregulin-1 dependent manner [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3071.
Abstract 3781: NF-κB classical and alternative signaling differentially regulate miRNA expression in ovarian cancer
Authors: Rahul D. Kamdar, Brittney S. Harrington, Soumya Korrapati, Emma Attar, Nathan Wong, Carrie D. House, Christina M. Annunziata
Journal: Cancer Research (2023)

Abstract The NF-κB signaling pathway has been shown to contribute to epithelial ovarian cancer (EOC) through its classical and alternative pathways, characterized by the RelA and RelB transcription factors respectively. Previous studies have highlighted the role of RelA in sustaining the proliferative cancer cell population, while RelB aids in promoting the survival of chemoresistant, stem-like tumor-initiating cells (TICs) that promote disease relapse. In further characterizing the downstream effects of NF-κB signaling on EOC, we hypothesize NF-κB signaling differentially regulates the expression of several microRNAs (miRNAs) to promote TIC survival and proliferation through its classical and alternative pathways. miRNAs comprise a subset of small, noncoding RNAs that regulate gene expression, making them amenable for therapeutic targeting. Inducible shRNA stably expressed in OV90 EOC cells to knockdown RelA or RelB were analyzed by miR-seq to identify the differential expression of miRNAs in cells grown in TIC vs adherent (adh) conditions. Several miRNAs were differentially expressed in these conditions with RelA or RelB knockdown; we identified and validated the expression of two candidate miRNAs: hsa-miR-452-5p and hsa-miR-335-5p. We observed the decreased expression of hsa-miR-452-5p when either RelA or RelB is knocked down, while also observing the increased expression of hsa-miR-335-5p when RelA is knocked down. By inhibiting miR-452-5p in conjunction with disrupting NF-κB activity, we found changes in cell viability, sphere formation, and expression of the stem cell marker ALDH. Understanding the role of miRNA signaling in the context of NF-κB will better define the transcriptional roles of RelA and RelB in EOC. Ongoing work will further characterize the downstream targets of these miRNAs as potential therapeutic targets. Citation Format: Rahul D. Kamdar, Brittney S. Harrington, Soumya Korrapati, Emma Attar, Nathan Wong, Carrie D. House, Christina M. Annunziata. NF-κB classical and alternative signaling differentially regulate miRNA expression in ovarian cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3781.
Abstract 3736: ZBTB46/FOXA2/HIF1A transcription activator complex promotes MCTP1-regulated neuroendocrine differentiation and epithelial-to-mesenchymal transition
Authors: Vu Thuy Dung Phan, Yu-Ching Wen, Wei-Yu Chen, Wei-Hao Chen, Kuo-Ching Jiang, Han-Ru Li, Van Thi Ngoc Tram, Zi-Qing Chen, Wan-Hsin Wang, Yen-Nien Liu
Journal: Cancer Research (2023)

Abstract Androgen deprivation therapy (ADT)-induced neuroendocrine differentiation (NED) is a well-known lethal subtype of prostate cancer (PCa) with a median survival rate of less than one year. Despite the increasing research attention on this variant of PCa, the underlying mechanism orchestrating therapy-related neuroendocrine prostate cancer (NEPC) remains elusive. We found that ADT-induced hypoxia-associated ZBTB46/FOXA2/HIF1A signaling enhances the multiple C2 domain transmembrane protein 1 (MCTP1), which promotes NED and epithelial-to-mesenchymal transition (EMT) of PCa. Mechanistically, ZBTB46 physically interacts with the HIF1A/FOXA2 complex, in which ZBTB46 may be a co-activator of the hypoxia-related FOXA2 transcription factor. Interestingly, this ZBTB46/FOXA2/HIF1A complex accumulates after hypoxia and functions as a transcriptional activator of MCTP1. Hypoxia-upregulated MCTP1 subsequently leads to NED and the increase in EMT, whereas the opposite is true for the knockdown of MCTP1 in PCa cells. Consistent with previous results, MCTP1 is highly expressed in high-grade castration-resistance prostate cancer (CRPC) and small-cell PCa (SCPC) tissues and is associated with NE markers and ZBTB46/FOXA2/HIF1A abundance. In this study, we explored the direct interaction of ZBTB46 protein with hypoxia-related FOXA2/HIF1A complex in PCa cells under hypoxic conditions, which promote MCTP1-driven EMT and NED. Our finding suggests that MCTP1 could be used as a biomarker for diagnosing NEPC and as a therapeutic target in clinical applications. Citation Format: Vu Thuy Dung Phan, Yu-Ching Wen, Wei-Yu Chen, Wei-Hao Chen, Kuo-Ching Jiang, Han-Ru Li, Van Thi Ngoc Tram, Zi-Qing Chen, Wan-Hsin Wang, Yen-Nien Liu. ZBTB46/FOXA2/HIF1A transcription activator complex promotes MCTP1-regulated neuroendocrine differentiation and epithelial-to-mesenchymal transition. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3736.
Abstract 3821: Berberine and emodin synergistically suppress the EGFR signaling cascade by targeting LAMB3 in pancreatic ductal adenocarcinoma
Authors: CAIMING XU, SILEI SUI, Keisuke Okuno, Silvia Pascual-Sabater, Cristina Fillat, Ajay Goel
Journal: Cancer Research (2023)

Abstract Background: Pancreatic cancer is one of the most devastating malignancies due to the development of intrinsic chemoresistance following chemotherapy. Extracellular matrix (ECM) proteins are intimately linked to cellular proliferation, invasion, and acquisition of chemoresistance in PDAC cells, making them promising therapeutic targets in this malignancy. Naturally occurring dietary botanicals, including berberine (BER) and emodin (EMO), have been shown to suppress ECM as one of the mechanism(s) for their anti-tumorigenic activity, along with their time-tested safety and cost-effectiveness. In addition, both BER and EMO are also known to induce apoptosis by modulating different pathways and regulating pro-apoptotic genes. Herein, we hypothesized that combined treatment with BER and EMO might exhibit synergistic anticancer efficacy by targeting the ECM and apoptotic pathways in PDAC cells. Methods: We undertook genomewide transcriptomic profiling analysis to identify critical ECM-related genes differentially expressed in PDAC. Subsequently, the TCGA dataset was analyzed to identify the prognostic significance of ECM-associated genes with overall survival (OS) and disease-free survival (DFS) in PDAC. A series of cell culture experiments were performed using PDAC cells, followed by their validation in patient-derived organoids to examine the synergistic anti-proliferative and chemopreventive effects of BER and EMO against PDAC. Results: Transcriptomic profiling identified that LAMB3 expression was significantly upregulated in PDAC tissue (P &amp;lt; 0.01) and was significantly associated with poor OS and DFS in PDAC patients (P &amp;lt; 0.01). The combination of BER and EMO displayed superior synergistic anti-tumor potential in PDAC cells vs. individual compounds, as revealed by cell proliferation, clonogenicity, migration, and invasion assays. The combination of BER and EMO also altered the expression of key proteins involved in cellular apoptosis, epithelial-mesenchymal-transition, and EGFR/ERK//AKT growth factor signaling pathways. Finally, these findings were successfully validated in PDAC patient-derived 3D organoids. Conclusions: We provide the first evidence that combined treatment with berberine and emodin exerts synergistic anti-cancer activity in PDAC, primarily regulated through the LAMB3-mediated interaction with other members of the EGFR-signaling pathway. Citation Format: CAIMING XU, SILEI SUI, Keisuke Okuno, Silvia Pascual-Sabater, Cristina Fillat, Ajay Goel. Berberine and emodin synergistically suppress the EGFR signaling cascade by targeting LAMB3 in pancreatic ductal adenocarcinoma. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3821.
Abstract 4102: attIL12-T cell therapy destructs cancer-associated fibroblasts and extracellular matrix in heterogenous osteosarcoma xenograft models
Authors: Jiemiao Hu, Alexander Lazar, Davis Ingram, Wei-Lien Wang, Wendong Zhang, Zhiliang Jia, Dristhi Ragoonanan, Jian Wang, Xueqing Xia, Kris Mahadeo, Richard Gorlick, Shulin Li
Journal: Cancer Research (2023)

Abstract The extracellular matrix (ECM) and cancer-associated fibroblasts (CAFs) play major roles in tumor progression, metastasis, and the poor response of many solid tumors to immunotherapy. CAF-targeted CAR-T cell therapy does not impair ECM components such as collagen. In this study, we investigated whether the recently invented attIL12-T cells could destroy CAFs to disrupt the ECM and uncovered the underlying mechanism by which attIL12-T cells penetrate stroma-enriched osteosarcoma tumors. RNA sequencing demonstrated that attIL12-T cell treatment altered ECM-related gene expression. Immunohistochemistry staining revealed disruption or elimination of high-density CAFs and ECM in osteosarcoma xenograft tumors following attIL12-T cell treatment and that CAF/ECM density was inversely correlated with T-cell infiltration. Other IL12-armed T cells, such as wild-type IL12-T or ttIL12-T cells, did not disrupt the ECM because this effect depended on the engagement between cell-surface vimentin (CSV) on the tumor cell surface and its ligand on the attIL12 -T cells. Mechanistic studies found that attIL12-T cell treatment elevated IFNγ production upon interacting with CSV+ tumor cells to suppress TGFβ secretion and in turn upregulate FAS-mediated CAF apoptosis. CAF destruction reshaped the tumor stroma to favor T cell infiltration and tumor destruction. Thus, this study unveiled a novel therapy—attIL12-T cells—for targeting CAFs/ECM. These findings are highly relevant to humans because CAFs are abundant in human osteosarcoma. Citation Format: Jiemiao Hu, Alexander Lazar, Davis Ingram, Wei-Lien Wang, Wendong Zhang, Zhiliang Jia, Dristhi Ragoonanan, Jian Wang, Xueqing Xia, Kris Mahadeo, Richard Gorlick, Shulin Li. attIL12-T cell therapy destructs cancer-associated fibroblasts and extracellular matrix in heterogenous osteosarcoma xenograft models. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4102.
Abstract 3760: MicroRNA-1 run down the growth and metastasis of small cell lung cancer
Authors: Parvez Khan, Jawed A. Siddiqui, Shailendra Kumar Maurya, Tamara Mirzapoiazova, Prakash G. Kshirsagar, Ramakanth Chirravuri Venkata, Sanjib Chaudhary, Ranjana Kanchan, Naveenkumar Perumal, Mahek Fatima, Md Arafat Khan, Asad Ur Rehman, Imayavaramban Lakshmanan, Sidharth Mahapatra, Prakash Kulkarni, Apar Kishor Ganti, Maneesh Jain, Ravi Salgia, Surinder Kumar Batra, Mohd Wasim Nasser
Journal: Cancer Research (2023)

Abstract Small cell lung cancer (SCLC) is a highly aggressive and metastatic lung cancer subtype with universal relapse and poor prognosis. The lack of potential drug targets limits targeted therapies for SCLC patients. To track down the potential therapeutic molecules in SCLC, we performed micro-RNA sequencing from the serum samples of SCLC patients and compared with the bulk RNA-sequencing data from SCLC tumor tissues. A consistent downregulation of microRNA-1 (miR-1) was observed in the SCLC patient serum samples, cell lines, and tumor tissues compared to their matched normal control. Overexpression of miR-1 in SCLC cell lines decreased cell growth and oncogenic signaling. Metastatic studies using the intracardiac injection model of SCLC cell lines showed that miR-1 overexpression decreases distant organ metastasis. Interestingly, the loss of function studies using miR-1Zip/sponging showed increased tumorigenesis and metastasis in SCLC subcutaneous and intracardiac xenografts. Mechanistic investigations revealed the CXCR4/FOXM1/RRM2 axis as a unique downstream target of miR-1 in SCLC. We found that FOXM1 transcriptionally regulates the RRM2 expression by directly binding to its promoter site, and miR-1 modulates these interactions through CXCR4. The results of the present study provided a strong preclinical rationale that miR-1 has a high potential for developing innovative SCLC therapies. Citation Format: Parvez Khan, Jawed A. Siddiqui, Shailendra Kumar Maurya, Tamara Mirzapoiazova, Prakash G. Kshirsagar, Ramakanth Chirravuri Venkata, Sanjib Chaudhary, Ranjana Kanchan, Naveenkumar Perumal, Mahek Fatima, Md Arafat Khan, Asad Ur Rehman, Imayavaramban Lakshmanan, Sidharth Mahapatra, Prakash Kulkarni, Apar Kishor Ganti, Maneesh Jain, Ravi Salgia, Surinder Kumar Batra, Mohd Wasim Nasser. MicroRNA-1 run down the growth and metastasis of small cell lung cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3760.
Abstract 3534: Interrogating the immune microenvironment of a novel mouse model of fusion positive rhabdomyosarcoma
Authors: Erin E. Resch, Kristianne M. Oristian, Elizabeth Mendes, Corinne M. Linardic, Brian H. Ladle
Journal: Cancer Research (2023)

Abstract Immunotherapies have been largely ineffective for pediatric soft tissue sarcomas, in particular for fusion-positive rhabdomyosarcoma (FP-RMS), characterized by the PAX-FOXO1 gene fusion. We are hampered by a paucity of predictive, immune-competent mouse models of this cancer with which to develop novel and effective immune-based therapies. To overcome this barrier, we analyzed the immune microenvironment of one of the few genetically-engineered mouse models (GEMM) of FP-RMS. Briefly, this model is driven by conditional knock-in expression of Pax3:Foxo1 at the endogenous Pax3 locus, with or without conditional loss of MST1/2 (gene name Stk4/3), a Hippo pathway mediator that is modulated by PAX3-FOXO1. These two genotypes demonstrate different disease penetrance and tumor location, with mice bearing loss of MST1/2 exhibiting higher tumor penetrance and favoring head and neck disease sites. We hypothesize that these models exhibit differences in tumor-immune interactions in the microenvironment that correlate with these phenotypic differences. We aim to characterize the immune microenvironment differences between these tumors and to establish this GEMM as a predictive, syngeneic model of FP-RMS. Tumors were generated spontaneously from a GEMM of FP-RMS. Tumors expressed PAX3-FOXO1 and either carried a conditional loss of MST1/2 (MSTnull) or native MST1/2 (MSTwt). We analyzed 8 formalin-fixed, paraffin-embedded (FFPE) tumors and 2 tumor-derived cell lines from these novel models. FFPE tumor samples were analyzed via immunohistochemistry (IHC) for CD3 (T cell marker) and CD11b (myeloid cell marker) and were scored for immune cell infiltration. Overall, tumors demonstrate poor CD3+ T cell infiltration with significantly higher infiltration of CD11b+ myeloid cells (p=0.0002); this trend is also seen within the individual MSTwt (p=0.0286) and MSTnull cohorts (p=0.0286). There was no significant difference in CD3+ T cell or CD11b+ myeloid cell density between the two genotypes. The drivers of this immune phenotype and the role of Hippo pathway signaling in mediating RMS tumor immune cell infiltration warrants further investigation. Additional ongoing studies are utilizing a spatial gene expression platform to visualize the spatially-preserved transcriptome of intact tumors to reveal potential pathways mediating the immune microenvironment. Citation Format: Erin E. Resch, Kristianne M. Oristian, Elizabeth Mendes, Corinne M. Linardic, Brian H. Ladle. Interrogating the immune microenvironment of a novel mouse model of fusion positive rhabdomyosarcoma. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3534.
Abstract 3823: Therapeutic potential of plant-derived nanovesicles for neuroendocrine prostate cancer
Authors: Amritha Sreekumar, Matthew Simmons, Tae Jin Lee, Ashok Sharma, Sharanjot Saini
Journal: Cancer Research (2023)

Abstract Background: Neuroendocrine prostate cancer (NEPC) is a highly lethal variant of prostate cancer (PCa) that often emerges after androgen receptor (AR)-targeted therapies such as enzalutamide and abiraterone. NEPC arises via trans-differentiation of prostate adenocarcinomas to neuronal lineage, a process referred to as ‘neuroendocrine trans-differentiation’ (NED), wherein prostate cancer cells show an altered expression of lineage markers such as decreased expression of AR and increased expression of neuronal markers. Currently, there is a lack of effective targeted therapies for NEPC. Current treatment options are limited to highly toxic platinum-based drugs. Hence, there is an urgent need to develop novel treatment strategies to treat NEPC. The focused objective of this study is to develop novel, non-toxic therapeutic intervention against NEPC. Towards this, we exploited the potential of plant-derived nanovesicles/extracellular vesicles as a novel therapeutic. Extracellular vesicles (EVs) are lipid-bilayer-delimited particles that are released from almost all types of cells, including plant cells, typically between 30-150 nm in size. Methods: EVs/nanovesicles were isolated from plant-derived sources by ultracentrifugation. Isolated nanovesicles were characterized by Nanoparticle Tracking Analyses and electron microscopy. After characterization, the effects of nanovesicles were tested in NEPC cell lines in vitro. Effects on cell viability and apoptosis were assessed by MTS assay and flow cytometry, respectively. To understand the mechanistic basis of EV induced alterations, next generation RNA sequencing was performed in control vs EV treated NCI-H660 cells on Illumina HiSeq platform. Significant targets were further validated by real time PCR and Western blot analyses. Results: Plant-derived nanovesicles reduced viability and induced apoptosis in NEPC cell lines. Genes involved in ECM-receptor interaction, focal adhesion, proteoglycans in cancer and small cell lung cancer genes were significantly impacted by these vesicles in NEPC cell line. Remarkably, nanovesicles led to significantly attenuated levels of key proneural transcription factors including ASCL1, BRN2 and SOX2. In addition, neuronal markers ENO2 and NCAM1 were downregulated suggesting that treatment with nanovesicles reverse the ‘cardinal’ genetic alterations that drive NEPC. Conclusion: Plant-derived nanovesicles can be employed as a novel treatment modality in neuroendocrine prostate cancer. Citation Format: Amritha Sreekumar, Matthew Simmons, Tae Jin Lee, Ashok Sharma, Sharanjot Saini. Therapeutic potential of plant-derived nanovesicles for neuroendocrine prostate cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3823.